Modafinil (1) is an α1-adrenergic agonist having psychostimulant activity, used for the treatment of idiopathic narcoplepsy.

At present, a number of known synthetic procedures (U.S. Pat. No. 4,177,290, FR 2582038 and EP 0283362) involve as key intermediate 2-[(diphenylmethyl)sulfenyl]acetic acid chloride (2), which is converted to amide (3) by treatment with ammonia and is then oxidized with hydrogen peroxide (scheme 1)

All these methods share the fact that oxidation with hydrogen peroxide is not selective to the sulfoxide, but also affords the sulfone (4):

U.S. Pat. No. 4,177,290 discloses an alternative process for the application on an industrial scale (scheme 2). Benzhydrol (5), thiourea (6) and 2-chloroacetic acid (7) are reacted in the presence of hydrobromic acid to obtain 2-[(diphenylmethyl)sulfenyl]acetic acid (8), which is oxidized with hydrogen peroxide to afford 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9). This is reacted with NaHCO3 and dimethyl sulfate and the resulting methyl ester (10) is converted to modafinil by treatment with ammonia.

However, the final product is difficult to purify from 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) and the methyl ester (10) thereof (two recrystallization steps are necessary) and the overall process yield is 41%. Moreover, the process involves the use of dimethyl sulfate, which is a cancerogenic reagent.
According to EP 0233106 and U.S. Pat. No. 4,927,855, concerning modafinil optically active forms, optically active 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) is converted to the methyl ester (10) with NaHCO3 and dimethyl sulfate, then is subjected to a transamidation reaction with ammonia.
WO 02/10125 discloses a method for the preparation of modafinil and its polymorphs by oxidation of 2-[(diphenylmethyl)sulfenyl]acetamide (3) with hydrogen peroxide in the presence of a mineral acid and of an alcohol or a phase transfer catalyst; this overcomes the problem of overoxidation. However, a recrystallization step is necessary to obtain the final product with pharmaceutically acceptable purity. It would therefore be advantageous to provide a method which not only prevents the sulfone formation, but also directly affords modafinil with a pharmaceutically acceptable purity.